α-Lipoic acid, also known as thioctic acid, is an eight-carbon fatty acid with a disulfide linkage joining the carbons 6 and 8 to form a 1,2-dithiolane ring. The acid forms optical isomers of which the isomer R-α-lipoic acid is the most biologically active. R-α-Lipoic acid is an essential nutrient and coenzyme that serves a variety of functions in the treatment and prevention of disease, including liver disease and diabetes. R-α-Lipoic acid is also useful as a nutraceutical, and one OF the recognized nutraceutical forms of the acid is the magnesium salt, magnesium di-R-α-lipoate.
A difficulty encountered in the synthesis of the magnesium salt of R-α-lipoic acid is the susceptibility of lipoic acid to polymerize at the sulfur atoms. The polymerized form is undesirable since it has a lower activity in the human digestive system than the unpolymerized acid or its salts. Polymerization of the acid can be reversed by treatment of the polymer with mercaptoethanol, as described by Barltrop, J. A., et al., “The Chemistry of 1,2-Dithiolane (Trimethylene Disulfide) as a Model for the Primary Quantum Conversion Act in Photosynthesis,” J. Am. Chem. Soc. 76: 4348-4367 (1954), or by treatment with various reagents including dithiothreitol and Ellman's reagent, as described by Samuel, N. K. P., et al., “Polymerized-Depolymerized Vesicles. Reversible Thiol-Disulfide-Based Phosphatidylcholine Membranes,” J. Am. Chem. Soc. 107: 42-47 (1985). Polymerization is also recognized as a problem in the conversion of α-lipoic acid to esters, which are disclosed as being useful as prodrugs and as precursors for other lipoic acid derivatives. Lawrence, L. J., et al., in United States Pre-Patent Application Publication US 2007/0055070 A1, propose the addition of L-cysteine as a polymerization inhibitor after the esterification reaction has been performed. A difficulty with all of these methods is that they introduce into the product a foreign species that may have a biological effect other than that sought from the α-lipoic acid, or simply dilute the α-lipoic acid unnecessarily.